The ability to maintain cognition despite the accumulation of AD pathology is known as cognitive or neural reserve. Theories of neural reserve include brain reserve capacity, and neural efficiency or compensation, i.e., brains differ in their response to the accumulation of AD pathology. In the initial funding period we found that many older persons without dementia or MCI meet pathologic criteria for AD, indicating that other factors must be involved in determining the extent to which AD pathology impairs cognition. We found that AD pathology often does not cause dementia in the absence of cerebral infarcts and Lewy bodies. Further, we found that loneliness, psychological distress, and cognitive activity were all related to incident AD, but were not related to measures of AD pathology, infarcts, or Lewy bodies, suggesting that other as yet unknown factors can alter brain reserve capacity. Finally, we found that the relation of AD pathology to cognition varied by social network size and level of processing resources (working memory and perceptual speed), consistent with neural efficiency or compensation. The proposed continuation of the Rush Memory and Aging Project, a community-based longitudinal epidemiologic study of risk factors for incident AD that includes brain donation at death, will build on findings from the initial funding period. The choice of risk factors was guided by the recommendations of the recent Cognitive and Emotional Health Project. The renewal is organized into three conceptual themes linking factors to incident AD and neuropathology. Specifically, we hypothesize that a) apolipoprotein E allele status, diabetes, and pulmonary function will be associated with incident AD via cerebrovascular pathology; b) the relation of neuropathology to cognition will vary by level of life course SES and physical activity; and c) depressive symptoms and parkinsonian signs will predict incident AD, but will actually represent early non-cognitive manifestations of AD pathology in neuronal populations subserving affective behavior and motor function, respectively. Since prevention is the best long-term strategy for reducing the burden of cognitive impairment in the U.S., and understanding the neurobiologic pathways linking risk factors to cognition is essential for the development of therapeutic interventions, the proposed study, with its involvement of community dwelling older men and women as subjects with a wide range of SES, is in a position to provide new knowledge critical to public health. The prevention of Alzheimer's disease provides the best long-term strategy to reduce the human and economic toll of disease, and understanding the biologic pathways linking risk factors to cognition is essential for developing therapeutic interventions. Thus, the proposed epidemiologic study of risk factors for AD that includes organ donation, with its involvement of community dwelling older men and women with a wide range of socioeconomic status, is in a position to provide new knowledge critical to public health.